Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia

Amit V. Khera, Hong Hee Won, Gina M. Peloso, Kim S. Lawson, Traci M. Bartz, Xuan Deng, Elisabeth M. van Leeuwen, Pradeep Natarajan, Connor A. Emdin, Alexander G. Bick, Alanna C. Morrison, Jennifer A. Brody, Namrata Gupta, Akihiro Nomura, Thorsten Kessler, Stefano Duga, Joshua C. Bis, Cornelia M. van Duijn, L. Adrienne Cupples, Bruce PsatyDaniel J. Rader, John Danesh, Heribert Schunkert, Ruth McPherson, Martin Farrall, Hugh Watkins, Eric Lander, James G. Wilson, Adolfo Correa, Eric Boerwinkle, Piera Angelica Merlini, Diego Ardissino, Danish Saleheen, Stacey Gabriel, Sekar Kathiresan

Research output: Contribution to journalArticlepeer-review


Background Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement. Objectives This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level. Methods Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database. Results Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers. Conclusions Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.

Original languageEnglish
Pages (from-to)2578-2589
Number of pages12
JournalJournal of the American College of Cardiology
Issue number22
Publication statusPublished - Jun 7 2016


  • coronary artery disease
  • gene sequencing
  • genetics
  • low-density lipoprotein cholesterol

ASJC Scopus subject areas

  • Medicine(all)
  • Cardiology and Cardiovascular Medicine


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